title: Prevention of radiation-induced salivary hypofunction following hKGF gene delivery to murine submandibular glands.
abstract: OBJECTIVE
  Salivary glands are significantly affected when head and neck cancer patients are treated by radiation. We evaluated the effect of human keratinocyte growth factor (hKGF) gene transfer to murine salivary glands on the prevention of radiation-induced salivary hypofunction.
  
  
  METHODS
  A hybrid serotype 5 adenoviral vector encoding hKGF (AdLTR(2)EF1α-hKGF) was constructed. Female C3H mice, 8 weeks old, were irradiated by single (15 Gy) or fractionated (6 Gy for 5 days) doses to induce salivary hypofunction. AdLTR(2)EF1α-hKGF or AdControl was administered (10(8) - 10(10) particles per gland) to both submandibular glands (SG) by retrograde ductal instillation before irradiation (IR). Salivary flow was measured following pilocarpine stimulation. Human KGF levels were measured by ELISA. SG cell proliferation was measured with bromodeoxyuridine labeling. Endothelial and progenitor or stem cells in SGs were measured by flow cytometry. The effect of SG hKGF production on squamous cell carcinoma (SCC VII) tumor growth was assessed.
  
  
  RESULTS
  In 3 separate single-dose IR experiments, salivary flow rates of mice administered the AdLTR(2)EF1α-hKGF vector were not significantly different from nonirradiated control mice (P > 0.05). Similarly, in 3 separate fractionated IR experiments, the hKGF-expressing vector prevented salivary hypofunction dramatically. Transgenic hKGF protein was found at high levels in serum and SG extracts. AdLTR(2)EF1α-hKGF-treated mice showed increased cell proliferation and numbers of endothelial cells, compared with mice treated with AdControl. hKGF gene transfer had no effect on SCC VII tumor growth ± radiation.
  
  
  CONCLUSIONS
  hKGF gene transfer prevents salivary hypofunction caused by either single or fractionated radiation dosing in mice. The findings suggest a potential clinical application.
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-1190, USA.
authors.forename: Changyu
authors.initials: C
authors.lastname: Zheng
authors.forename: Ana P
authors.initials: AP
authors.lastname: Cotrim
authors.forename: Anne
authors.initials: A
authors.lastname: Rowzee
authors.forename: William
authors.initials: W
authors.lastname: Swaim
authors.forename: Anastasia
authors.initials: A
authors.lastname: Sowers
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Baum
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000532:radiotherapy; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000008:administration & dosage / Q000235:genetics* / Q000502:physiology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000532:radiotherapy; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D011833:Radiation Injuries, Experimental / Q000150:complications / Q000517:prevention & control*; D011878:Radiotherapy / Q000009:adverse effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D012466:Salivary Gland Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D012469:Salivary Glands / Q000378:metabolism / Q000503:physiopathology* / Q000528:radiation effects; D013363:Submandibular Gland / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D014407:Tumor Cells, Cultured
chemical_list: C496453:FGF7 protein, human; D011994:Recombinant Proteins; D051523:Fibroblast Growth Factor 7